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Updated: Apr 21, 2026
A Preclinical Mouse Model of Osteosarcoma to Define the Extracellular Vesicle-mediated Communication Between Tumor and Mesenchymal Stem Cells
Published on: May 6, 2018
Manganese-potentiated cGAS-STING activation with ATM/PRMT5 inhibition remodels the immunosuppressive microenvironment
Zhaochen Tong1, Yuezhan Li2, Lingpu Zhang3
1Department of Spine Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan, 410013, PR China.
Abstract:
Osteosarcoma (OS), the most common malignant bone tumor, remains challenging to treat because of poor drug delivery to bone tissue and limited response to immunotherapy. To overcome these hurdles, we developed a bone-targeted, glutathione (GSH)-responsive polymeric nanoparticle (NPALN/Mn-AP) that chelates manganese (Mn) and delivers an ATM inhibitor (AZD0156) and a PRMT5 inhibitor (GSK3326595). By functionalizing this nanoplatform with alendronate (ALN) into NPALN/Mn-AP, we achieve preferential accumulation in bone tumors. Upon cellular uptake, elevated intracellular GSH levels in OS cells trigger the controlled release of both inhibitors. Inhibiting ATM and PRMT5 amplifies DNA damage and activates the cGAS-STING pathway, while Mn ions further enhance this innate immune signaling by promoting cytosolic DNA sensing. Together, these effects reshape the tumor microenvironment toward a more immune-responsive state and promote antitumor immunity in osteosarcoma. In vivo studies demonstrate that NPALN/Mn-AP significantly inhibits OS progression and boosts systemic immune responses. This dual-action, bone-specific nanotherapeutic platform synchronized DNA-repair inhibition and Mn-enhanced immune-stimulation, offering a promising new approach for effective osteosarcoma treatment.
Insights
A novel nanoparticle delivers dual inhibitors to bone tumors, enhancing DNA damage and immune response for effective osteosarcoma treatment. This bone-targeted therapy shows significant promise in preclinical studies.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Osteosarcoma (OS) presents treatment challenges due to poor drug delivery and limited immunotherapy response.
- Developing targeted therapies is crucial for improving outcomes in bone cancer.
- Nanoparticle-based drug delivery offers potential solutions for localized cancer treatment.
Purpose of the Study:
- To develop a bone-targeted, glutathione-responsive nanoparticle (NPALN/Mn-AP) for osteosarcoma treatment.
- To co-deliver ATM and PRMT5 inhibitors to enhance DNA damage and immune signaling.
- To investigate the therapeutic efficacy of this nanoplatform in preclinical osteosarcoma models.
Main Methods:
- Fabrication of alendronate-functionalized nanoparticles (NPALN/Mn-AP) co-delivering ATM and PRMT5 inhibitors.
- Utilizing manganese (Mn) chelation to enhance immune signaling.
- Evaluating nanoparticle accumulation, drug release, and cellular effects in osteosarcoma cells.
- Assessing *in vivo* efficacy, including tumor inhibition and systemic immune response modulation.
Main Results:
- NPALN/Mn-AP demonstrated preferential accumulation in bone tumors.
- Elevated intracellular glutathione triggered controlled release of both inhibitors.
- Inhibition of ATM and PRMT5 amplified DNA damage and activated the cGAS-STING pathway.
- Manganese ions enhanced innate immune signaling, promoting cytosolic DNA sensing.
- *In vivo* studies showed significant inhibition of osteosarcoma progression and boosted systemic immune responses.
Conclusions:
- The developed nanotherapeutic platform effectively targets bone tumors and co-delivers therapeutic agents.
- This dual-action strategy synchronizes DNA-repair inhibition and manganese-enhanced immune stimulation.
- NPALN/Mn-AP represents a promising new approach for osteosarcoma treatment by reshaping the tumor microenvironment and promoting antitumor immunity.
